RU2543166C2 - Age-specific diagnostic technique for various forms of connective tissue dysplasia syndrome - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: known manifestations of connective tissue dysplasia (CTD) and additional reproductive manifestations of CTD are detected and rated to assign each CTD manifestation with certain points depending on the child's or adult's age. The derived points are summed up. If the total score exceeds a bottom limit for the respective age group, then a non-differentiated CTD syndrome is diagnosed. If the total score exceeds the bottom limit for the respective age group, then a differentiated CTD syndrome is diagnosed.

EFFECT: technique provides the objective differential diagnostics of various forms of CTD in any age group at the early stages of the disease that in turn enables the timely corrective therapy enabling the delay of CTD manifestations.

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Description

The invention relates to medicine, namely to pediatrics, therapy, pediatric and general surgery, for the diagnosis of connective tissue dysplasia syndrome, as well as diseases developing against its background, and can be put into practice in clinics, hospitals and rehabilitation institutions.

The number of disorders associated with dysplastic processes, grouped into syndromes and phenotypes similar in external and visceral features, is very large. Identification of certain types of connective tissue dysplasia due to the difficulties of conducting molecular genetic studies is extremely difficult, therefore, the principles of grouping syndromes and phenotypes based on the proximity of their phenotypic manifestations are used.

Such a grouping is based on algorithms based on generally accepted approaches and agreed criteria. The revised Ghent criteria (International recommendations for the diagnosis of Marfan syndrome - Geth criteria (Ghent criteria, De Raere A. et al., 1996) and Loeys BL et al., 2010 introduced the concept of "systemic involvement of connective tissue" ( ICTS), which is assessed by the number of points assigned to the most specific signs of dysembryogenesis, the approach to the diagnosis of connective tissue dysplasia (DST) has changed in recent years.The Committee of Experts of GFCF has proposed the concept of dysplastic syndromes and phenotypes (DSiF), as well as algorithms and diagnostics (All-Russian Scientific Society of Cardiology (GFCF) // Russian recommendations for the concept of dysplastic syndromes and phenotypes, 2009). These algorithms do not take into account the age-related dynamics of phenotypic signs of dysembryogenesis (DEG), which affects the diagnostic significance of individual signs and complicates the diagnosis of hereditary connective disorders tissue (HHCT) (Berlin nosology of hereditary connective tissue disorders (Beighton P. et al., 1988).

In addition to the described dysplastic phenotypes related to Ehlers-Danlo syndrome, Marfan syndrome, etc., there are dysplastic phenotypes that are combined into a group of undifferentiated connective tissue dysplasia (NDST). NDCT is exhibited when the set of clinical signs does not fit into any of the hereditary monogenic diseases (International guidelines for the diagnosis of Ehlers-Danlo syndrome - Villefranche criteria (Villefranche criteria, Beighton P. et al., 1998).

The phenotypic manifestations of DST include not only a specific appearance and cosmetic defects, but also severe pathological changes in the internal organs and musculoskeletal system.

Known are described in the literature according to various authors for the diagnosis of DST by clinical and morphological manifestations, these include:

skeletal changes: asthenic physique, dolichostenomelia (disproportionately long limbs), arachnodactyly (long thin fingers), various types of chest deformity, scoliosis, kyphosis and lordosis of the spine, “straight back” syndrome, flatfoot, etc. These changes are associated with a violation of the structure of the cartilage and delayed maturation of the epiphyseal growth zone, which is manifested by lengthening of the tubular bones. At the heart of chest deformities is the inferiority of the costal cartilage;

changes in the skin: hyperelasticity, thinning, a tendency to trauma and the formation of keloid scars or scars in the form of "tissue paper";

changes in the muscle system: a decrease in muscle mass, including cardiac and oculomotor muscles, which leads to a decrease in the contractility of the myocardium and myopia;

joint pathology: excessive mobility (hypermobility), a tendency to dislocations and subluxations, due to weakness of the ligamentous apparatus;

pathology of the organs of vision: one of the most frequent manifestations of DST, is represented by myopia of various degrees, dislocation of the lens, an increase in the length of the eyeball, flat cornea, blue sclera syndrome;

lesions of the cardiovascular system: very diverse and often determine the prognosis. Anatomical changes in heart valves are usually diagnosed: dilatation of the fibrous rings and prolapse, abnormal chords, expansion of the ascending aorta and pulmonary artery, followed by the formation of saccular aneurysm. In addition, deformations of the chest and spine lead to the development of various types of thoracodiaphragmatic heart;

vascular damage: manifested by aneurysmal dilatation of arteries of medium and small caliber and - very often - varicose veins of the lower extremities;

bronchopulmonary lesions: concern both the bronchial tree and the alveoli. Most often, bronchiectasis, simple and cystic hypoplasia, bullous emphysema and spontaneous pneumothorax are diagnosed;

kidney pathology: nephroptosis and renovascular changes.

In the available literature, according to various authors, the following syndromic disorders are described. ^one

Syndrome of neurological disorders: autonomic dysfunction (neurocircular dystonia, panic attacks and others (occurs in 97% of cases with differentiated DST and 78% of undifferentiated DST).

Asthenic syndrome: decreased performance, worsening tolerance to physical and psycho-emotional stress, increased fatigue. Asthenic syndrome is detected in preschool and especially brightly - at school, adolescence and young age, accompanying patients with DST throughout life.

Valvular syndrome: isolated and combined heart valve prolapse, myxomatous valve degeneration. More often it is represented by mitral valve prolapse (MVP) (up to 70%), less often - by tricuspid or aortic valve prolapse, expansion of the aortic root and pulmonary trunk; aneurysms of the Valsalva sinuses. In some cases, the revealed changes are accompanied by regurgitation phenomena, which affects the indicators of myocardial contractility and volumetric parameters of the heart. Valvular syndrome begins to form in childhood (4-5 years).

Thoracodiaphragmatic syndrome: asthenic form of the chest, chest deformities (funnel-shaped, keeled), spinal deformities (scoliosis, kyphoscoliosis, hyperkyphosis, hyperlordosis, etc.), changes in standing and excursion of the diaphragm. Among patients with DST, the most common is funnel chest deformity, the second most frequent is keeled, and the asthenic form of the chest is most rarely detected. The beginning of the formation of thoracodiaphragmatic syndrome occurs in early school age, the distinctness of manifestations - at the age of 10-12 years, the maximum severity - for a period of 14-15 years. In all cases, funnel-shaped deformity is noted by doctors and parents 2-3 years earlier than keeled. The presence of thoracodiaphragmatic syndrome determines a decrease in the respiratory surface of the lungs, deformation of the lumen of the trachea and bronchi; displacement and rotation of the heart, "torsion" of the main vascular trunks.

Vascular syndrome: damage to the arteries of the elastic type: idiomatic expansion of the wall with the formation of saccular aneurysm; damage to the arteries of muscle and mixed types: bifurcation-hemodynamic aneurysms, dolichoectasia of elongated and local extensions of the arteries, pathological tortuosity up to loop formation; vein damage (pathological tortuosity, varicose veins of the upper and lower extremities, hemorrhoidal and other veins); telangiectasias; endothelial dysfunction. Vascular changes are accompanied by an increase in tone in the system of large, small arteries and arterioles, a decrease in the volume and speed of filling the arterial bed, a decrease in venous tone, and excessive deposition of blood in the peripheral veins. Vascular syndrome manifests in adolescents and young adults, progressing with increasing age of patients.

Changes in blood pressure: idiopathic arterial hypotension.

Thoracodiaphragmatic heart: asthenic, constrictive, pseudostenotic, pseudodilation options, thoracodiaphragmatic pulmonary heart. The formation of a thoracodiaphragmatic heart occurs simultaneously with the manifestation and progression of deformation of the chest and spine, against the background of valvular and vascular syndromes.

Arrhythmic syndrome: ventricular extrasystole of various gradations; multifocal, monomorphic, less often polymorphic, monofocus atrial extrasystole; paroxysmal tachyarrhythmias; pacemaker migration; atrioventricular and intraventricular blockade; anomalies of the impulse along additional paths; ventricular pre-excitation syndrome; Q-T interval lengthening syndrome. The detection rate of arrhythmic syndrome is about 64%. The source of heart rhythm disturbance may be a focus of impaired metabolism in the myocardium. In violation of the structure and function of connective tissue, a similar substrate of biochemical genesis is always present. Valve syndrome can serve as a cause of heart rhythm disturbances in DST. The occurrence of arrhythmias in this case may be due to the strong tension of the mitral valves containing muscle fibers, capable of diastolic depolarization with the formation of bioelectric myocardial instability. In addition to the cardiac causes of the origin of arrhythmias in DST, there are extracardiac, caused by a violation of the functional state of the sympathetic and vagus nerves, mechanical irritation of the heart shirt with a deformed chest bone.

Sudden death syndrome: changes in the cardiovascular system with DST, determining the pathogenesis of sudden death, valve, vascular, arrhythmic syndromes. According to observations in all cases, the cause of death is directly or indirectly associated with morphofunctional changes in the heart and blood vessels: in some cases, it is caused by a gross vascular pathology that can be easily ascertained at autopsy (ruptures of aortic aneurysms, cerebral arteries, etc.), in other cases, sudden death caused by factors that are difficult to verify on a sectional table (arrhythmic death).

Bronchopulmonary syndrome: tracheobronchial dyskinesia, tracheobronchomalacia, tracheobronchomegaly, ventilation disorders (obstructive, restrictive, mixed disorders), spontaneous pneumothorax. Modern authors describe bronchopulmonary disorders in DST as genetically determined violations of the architectonics of the lung tissue in the form of destruction of the interalveolar septa and underdevelopment of elastic and muscle fibers in small bronchi and bronchioles, leading to increased extensibility and decreased elasticity of the lung tissue.

Immunological disorders syndrome: immunodeficiency syndrome, autoimmune syndrome, allergic syndrome. The functional state of the immune system in DST is characterized by both activation of the immune mechanisms that maintain homeostasis and their insufficiency, leading to impaired ability to adequately release the body from foreign particles and, consequently, to the development of recurrent infectious and inflammatory diseases of the bronchopulmonary system. Immunological disorders in some patients with DST include an increase in blood levels of immunoglobulin E.

Visceral syndrome: nephroptosis and dystopia of the kidneys, ptosis of the gastrointestinal tract, pelvic organs, dyskinesia of the gastrointestinal tract, duodenogastric and gastroesophageal refluxes, insolvency of the sphincter, esophageal diverticulum, hiatal hernia; genital ptosis in women.

Syndrome of the pathology of the organ of vision: myopia, astigmatism, hyperopia, strabismus, nystagmus, retinal detachment, dislocation and subluxation of the lens. Disorders of accommodation are manifested in different periods of life, in the majority of examined in school years (8-15 years) and progresses to 20-25 years.

Hemorrhagic hematomesenchymal dysplasias: hemoglobinopathies, Randu-Osler-Weber syndrome, recurrent hemorrhagic (hereditary platelet dysfunction, von Willebrand syndrome, combined variants) and thrombotic (platelet hyperaggregation, primary antiphospholipid syndrome, protein resistance syndrome).

Foot pathology syndrome: clubfoot, flat feet (longitudinal, transverse), hollow foot. Foot pathology syndrome is one of the earliest manifestations of connective tissue failure. The most common is a transverse-flattened foot (transverse flatfoot), in some cases combined with a deviation of 1 finger outward (hallus valgus) and longitudinal flatfoot with pronation of the foot (flat valgus foot).

Joint hypermobility syndrome: joint instability, dislocation and subluxation of joints. Joint hypermobility syndrome in most cases is determined already in early childhood. Maximum joint hypermobility is observed at the age of 13-14 years, by 25-30 years, the prevalence decreases by 3-5 times. The incidence of joint hypermobility is significantly higher among patients with severe DST.

Vertebrogenic syndrome: juvenile osteochondrosis of the spine, intervertebral hernia, vertebrobasillar insufficiency; spondylolisthesis.

Cosmetic syndrome: dysplastic-dependent dysmorphies of the maxillofacial region (malocclusion, Gothic palate, severe facial asymmetries); O- and X-shaped deformities of the limbs; changes in the skin (thin, translucent and easily vulnerable skin, increased skin extensibility, a seam in the form of “tissue paper”). Cosmetic DST syndrome is significantly aggravated by the presence of small developmental abnormalities detected in the vast majority of patients with DST.

Mental disorders: neurotic disorders, depression, anxiety, hypochondria, obsessive-phobic disorders, anorexia nervosa. It is known that patients with DST form a group of increased psychological risk, characterized by a reduced subjective assessment of their own abilities, level of claims, emotional stability and performance, increased level of anxiety, vulnerability, depression, conformism.

Phenotypic signs of DST may be absent at birth or have very slight severity even in cases of differentiated forms of DST, which manifest during life. Differentiated DST is characterized by a certain type of inheritance, a clearly defined clinical picture, and in some cases by an established and well-studied gene or biochemical defect: Ehlers-Danlo, Marfan and other syndromes. Undifferentiated connective tissue dysplasia (NDST) is not a single nosological unit, but a heterogeneous a group in which a set of clinical signs does not fit into any of the hereditary monogenic diseases (Kadurina T.I., Gorbunova V.N. DST - St. Petersburg, 2009 - p. 7). Most often, NDST is manifested by two well-known phenotypes: marfanoid and elersiform (Kadurina T.I., Gorbunova V.N. DST - St. Petersburg, 2009 - p. 9).

Signs of dysplasia can be seen in childhood (distinct signs appear by the age of 5) and, with optimal rehabilitation therapy, prevent its progression. Over the years, the number of signs of DST and their severity is growing.

A known method for the integrated assessment of morphotypic characters associated with connective tissue dysplasia (RF Patent No. 2341184, class AB 5/00, 2008, bull. No. 35), where only those of the known morphotypic characters associated with DST are selected for evaluation, which can be measured objectively, with each attribute being assigned a specific quantitative indicator, namely: Quetelet index, Pinier index, general flexibility indicator, Chizhin index, height of the skin fold on the hand, index according to the “thumb test”, showing atelier according to the “wrist test”, the ratio of the length of the third finger of the hand to the length of the hand, the degree of mobility in the joints of the hand, the extension angle in the metacarpophalangeal joint of the fifth finger, the extension angle in the elbow joint, the extension angle in the knee joint. Next, a quantitative assessment is made of the severity of each of the determined features. As such an assessment, the value of the relative deviation of the corresponding indicator in the subject from the average norm of this indicator, expressed in values of the standard deviation, is taken.

The disadvantage of this method is its narrow focus in diagnosis, the lack of a comprehensive assessment of the patient's health. The method evaluates only the morphological manifestations of DST syndrome, and only from the musculoskeletal system, and, first of all, is aimed at studying the syndrome of joint hypermobility, not taking into account the manifestations of DST syndrome from other organs and systems. In addition, the disadvantage of this method is its bulkiness of the formula and the complexity of the quantitative determination. In calculating the formula, 12 parameters are used, each of which, in turn, requires a quantitative calculation. As a result, the process of diagnosis is delayed and is of little use in practical work. The method does not reveal gender differences in the manifestation of the syndrome, meanwhile, indicators such as the extension angle in the elbow joint, the extension angle in the knee joint, the ratio of the length of the third finger to the length of the hand are different in people of the opposite sex; an increase in these values is normally characteristic of the female sex. But the average, “normal” degree of joint mobility is significantly different in age, gender and ethnic groups. In particular, when examining healthy individuals in Moscow aged 16–20 years, more than half among women and more than a quarter among men showed a degree of HMS (joint hypermobility) exceeding 4 points by Beighton (Server Medical Library) A.G. Belenky Joint hypermobility syndrome in general practice. - Section: Therapy / Publ. May 23, 2007 (International Recommendations for Diagnosing Joint Hypermobility Syndrome (CMS) - Brighton Criteria, 1998 with their subsequent revision R. Grahame (2000).

A known method for the diagnosis of connective tissue dysplasia (RF Patent No. 2400137, class A61B 5/107, 2010, bull. No. 27), taken as a prototype, in which an external examination of the eye area was selected for diagnosis. When a short palpebral fissure is detected - from 26 to 23 mm - connective tissue dysplasia is diagnosed. The method allows to increase the accuracy of the diagnosis of DST. It was found that for all patients with DST, regardless of the length of the palpebral fissure, a greater number of ophthalmic changes is characteristic than in practically healthy individuals. In the presence of a short palpebral fissure, dominance is observed in the number of ocular signs of dysmorphogenesis over a group without this symptom, both with small and significant severity. The prevalence of external somatic stigma over control was in all the presented groups, as well as manifestations of dysembryogenesis throughout the body. An examination by an ophthalmologist revealed changes in the palpebral fissures, eyelids, sclera, iris, lens, retinal vessels, visual impairment combined with skeletal and cardiological changes, hypermobility of joints, stigmas of dysembryogenesis.

The disadvantage of the prototype is its narrow specificity, namely, ophthalmic changes: short (23 mm) and narrow (9 mm) palpebral fissures, ocular hypertelorism, epicanthus, ptosis of the eyelids, blue sclera, heterophory, tortuosity of the conjunctival vessels of the sclera, folds of the conjunctiva above the lower eyelid hypoplasia of the superficial mesodermal leaf of the iris, partial destruction of the pigmented fringe, point opacities in the anterior cortical layers of the lens, linear opacification of the posterior lens capsule, spindle-shaped cataract, and Mittendorf with rudimentary hyaloid artery filamentous floater, change caliber retinal vessels around the optic disc pigment accumulation, complex inverse hyperopic astigmatism of both eyes. And also the fact that with pronounced shortening of the palpebral fissure, there was a greater level of stigmatization of the body as a whole compared with patients with DST who did not have this symptom.

The technical result of the proposed method is to identify new criteria, namely, a visual decrease in the volume of gonads and a delay in the development of secondary sexual characteristics depending on gender and age. A decrease in the total volume of the testes and ovaries is characteristic of DST syndrome, which is confirmed by the results of ultrasound in the study.

The problem is solved by the claimed method of age-related diagnosis of connective tissue dysplasia syndrome, namely, in the diagnosis of DST syndrome, a decrease in the total volume of the testicles, ovaries is revealed, which is confirmed by ultrasound results for all age periods. Signs of DST are evaluated depending on their permanent nature at 3 points or periodic - at 1 point. Manifestations of DST in organs and systems are represented by permanent signs of 2 points. If the syndrome includes more than two persistent symptoms, then the number of points in the syndrome rises to 3. Each age group is assigned its own minimum number of points, the set of which puts the syndrome of undifferentiated connective tissue dysplasia.

As a new morphological sign of DST syndrome, criteria are used from the reproductive system (symptoms of hypogonadism, delayed sexual development), among them constant is the total volume of gonads (genital glands) - testicular in boys and men, ovarian - in girls and women, determined during ultrasound examination of the internal genital organs. The volume of gonads is an objective morphological criterion of fertility and constitutionally determined human hormonal activity. If the total score exceeds the upper limit, for example, 9 points in newborns, one of the differentiated syndromes of connective tissue (Ehlers-Danlo, Marfan, etc.) is exposed. For the diagnosis of DST syndrome, a decrease in testicular volume in the scrotum in boys is visually determined using age criteria supported by ultrasound. In girls, a delay in the formation of secondary sexual characteristics, ovarian hypoplasia, also confirmed by the results of U3 diagnostics, is revealed in the history. The decrease in the total volume of the testes and ovaries as a criterion for connective tissue dysplasia, obtained as a result of this study, forms a new addition, not indicated in previous studies, in theory. It is based on the definition of connective tissue dysplasia as a syndrome associated with a delay in the formation of the reproductive system, a decrease in the hormonal level that occurs as a result of embryologically formed insufficiency of the gonads under the influence of the hormones of the mother and fetus.

In addition, in order to take into account the symptoms of connective tissue dysplasia that occur in early childhood, this study proposes the following system for recording signs of DST in children. In the early age groups (neonatal period, infancy, pre-school age, i.e. up to 6 years old, when the child cannot yet identify all dysplasia syndromes by age), it is proposed to use a quantitative quantitative assessment of only the symptoms of DST, and from the age of seven age - to assess dysplasia syndromically, because from this age many syndromic manifestations are manifested.

Thus, the list of persistent symptoms of DST (Kadurina T.I., Gorbunova V.N. DST - St. Petersburg, 2009 - pp. 50-54) introduced new additional criteria from the reproductive system, which are evaluated as well as other recurrent (transient) symptoms of DST revealed during the history taking are 1 point, and permanent symptoms are 2 points. Such a differentiated approach ensures the priority of persistent symptoms over periodic ones and allows a more objective approach to the identification of DST syndrome.

The advantage of the proposed new point system is that this system can be used in any age group, starting from the neonatal period to senile age. The inventive method for the diagnosis of DST in children and adults makes it possible to identify the course of a given condition of connective tissue at earlier stages of the disease, prescribe corrective therapy, which will slow down the progression of the manifestations of connective tissue dysplasia in the future.

The proposed method can be used in any medical institution, is readily available, non-invasive and applicable in medical practice. The claimed invention can be recommended for mass prophylactic programs in population and epidemiological studies, because meets the requirements for screening.

In addition, for each age period (table 1), a different score is used, since according to the results of this study in primary school age the number of symptoms of CTD is relatively small; then the number of symptoms (and, accordingly, points) increases, and in the elderly and senile age - on the contrary, decreases. So, for example, in newborns (from 0 to 3-4 weeks), the minimum amount of points sufficient to detect DST syndrome is 4 points, and the maximum is 9 points.

All groups of symptoms and syndromes included in the DST syndrome are divided into constant, accompanying the patient throughout life, and periodic, manifested in certain age periods. When diagnosing DST syndrome, signs are distinguished that are characterized by polymorphism, are most often found in syndromic disorders and are permanent signs:

- asthenic syndrome: decreased performance, increased fatigue, worsening tolerance to physical and psycho-emotional stress;

- valve syndrome: additional chord, isolated and combined prolapse of heart valves;

- thoracodiaphragmatic syndrome: asthenic form of the chest, chest deformities (funnel-shaped, keeled), spinal deformities (scoliosis, kyphoscoliosis, hyperkyphosis, hyperlordosis, etc.), changes in standing and excursion of the diaphragm;

- vascular syndrome: damage to the arteries of the elastic type: idiomatic expansion of the wall with the formation of saccular aneurysm; damage to the arteries of muscle and mixed types: bifurcation-hemodynamic aneurysms, dolichoectasia of elongated and local extensions of the arteries, pathological tortuosity up to loop formation; vein damage (pathological tortuosity, varicose veins of the upper and lower extremities, hemorrhoidal and other veins); telangiectasias; endothelial dysfunction; arteriovenous malformation, vegetative-vascular dysfunction, heart attack, stroke;

- arrhythmic syndrome: ventricular extrasystole of various gradations; multifocal, monomorphic, less often polymorphic, monofocus atrial extrasystole; paroxysmal tachyarrhythmias; pacemaker migration; atrioventricular and intraventricular blockade; anomalies of the impulse along additional paths; ventricular pre-excitation syndrome;

- bronchopulmonary syndrome: tracheobronchial dyskinesia, tracheobronchomalacia, tracheobronchomegaly, ventilation disorders (obstructive, restrictive, mixed disorders), spontaneous pneumothorax;

- visceral syndrome: nephroptosis and dystopia of the kidneys, ptosis of the gastrointestinal tract, pelvic organs, dyskinesia of the gastrointestinal tract, duodenogastric and gastroesophageal refluxes, insolvency of the sphincter, esophageal diverticulum, hiatal hernia; genital ptosis in women;

- syndrome of pathology of the organ of vision: myopia, astigmatism, hyperopia, squint, nystagmus, retinal detachment, dislocation and subluxation of the lens;

- Foot pathology syndrome: clubfoot, flat feet (longitudinal, transverse), hollow foot;

- joint hypermobility syndrome: articular (arthralgia and myalgia, acute post-traumatic articular or periarticular pathology, accompanied by synovitis, tenosynovitis or bursitis, periarticular lesions (tendonitis, epicondylitis, other enthesopathies, bursitis, tunnel syndrome), early (early) nodosa polyosteoarthrosis, secondary lesion of large joints (knee, hip), thoracalgia and lumbalgia, symptomatic longitudinal, transverse or combined flat and its complications: medial tenosynovitis in the ankle joint, hallux valgus and secondary ankle arthrosis (longitudinal flatfoot), posterolateral bursitis, thalalgia, “corns”, “hammer-like” deformation of the fingers, Hallux valgus (transverse flat-footedness). joints, tendency to frequent injuries, dislocation and subluxation of joints);

- vertebrogenic syndrome: juvenile osteochondrosis of the spine, intervertebral hernias, vertebrobasillar insufficiency, spondylolisthesis;

- cosmetic syndrome: dysplastic-dependent dysmorphies of the maxillofacial region (malocclusion, Gothic palate, severe facial asymmetries); O- and X-shaped deformities of the limbs; changes in the skin (thin, translucent and easily vulnerable skin, increased skin extensibility, a seam in the form of “tissue paper”);

- mental disorders: neurotic disorders, anxiety, hypochondria, anorexia nervosa, reduced subjective assessment of their own abilities, level of claims, emotional stability and performance, vulnerability, depression, conformism.

These violations are characteristic of all age periods according to the classification of age groups of the population (International Symposium on Age Periodization; Moscow, 1965; Mazurin A.V., Vorontsov I.M. Propaedeutics of childhood diseases. - M. Medicine, 1985 - .twenty). Syndromes and symptoms of organs and systems, as well as manifestations of DST in the reproductive system are presented in Table 1, with the help of which, depending on the age of the patient, one can find certain signs of DST, including in the reproductive system.

To obtain the minimum number of points in undifferentiated dysplasia of the connective tissue, the identified constant and intermittent symptoms from the neonatal period are summarized.

Table 1 Age-related clinical manifestations of connective tissue dysplasia No. Age Manifestations of DST (in points) Manifestations of DST in the reproductive system (in points) one. newborn from 0 to 3-4 weeks: from 4 to 9 points umbilical hernia - 1b, dysplasia of the hip joints - 1b, installation torticollis - 1b, funnel chest - 1b micropenis - 1b, testicular hypoplasia - 3b, hypospadias-1b 2. chest from 3-4 weeks to 12 months: from 7 to 11 points umbilical hernia - 1b, hip dysplasia - 1b, funnel chest - 1b,
installation torticollis - 1b, regurgitation and vomiting syndrome - 1b, hemangiomas - 1b micropenis - 1b, testicular hypoplasia - 3b,
hypospadias - 1b, synechia of the labia-1b 3. preschool from 1 g to 3 years: from 8 to 13 points hernia of the anterior abdominal wall -1b,
chronic constipation - 1b, flat-valgus feet - 1b, funnel chest - 1b, regurgitation and vomiting syndrome - 1b, hemangiomas - 1b, prolapse of the rectum - 1b micropenis - 1b, testicular hypoplasia - 3b, ovarian hypoplasia -3b,
hypospadias - 1b, synechia of the labia -1b, cryptorchidism-1b four. preschool from 4 to 6 years: from 9 to 14 points chronic constipation - 1b, nocturnal enuresis - 1b, flat-valgus feet - 1b, impaired posture - 1b, mitral valve prolapse - 3b, habitual dislocation of joints - 1b testicular hypoplasia - 3b, ovarian hypoplasia - 3b,
phimosis - 1b, anorchism - 1b, testicular hypermobility -1b, 5. junior school from 7 to 11 years: from 11 to 26 points visceral syndrome - 2b, hypermobility of joints - 3b, valve syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome -2b, pathology of the organs of vision - 2b, cosmetic syndrome - 2b, bronchopulmonary syndrome - 2b, foot pathology syndrome - 2b, arrhythmic syndrome - 2b phimosis - 1b, testicular hypoplasia - 3b, ovarian hypoplasia - 3b 6. senior school from 12 to 17-18 years: from 12 to 33 points visceral syndrome - 2b, hypermobility of joints - 3b, vascular syndrome - 2b, valve syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome -2b, visual pathology - 2b, cosmetic syndrome - 2b, bronchopulmonary syndrome - 2b, foot pathology syndrome - 2b, arrhythmic syndrome - 2b testicular hypoplasia - 3b, ovarian hypoplasia - 3b, uterine hypoplasia - 1b, varicocele - 1b, delayed sexual development - 2b, amenorrhea - 1b, amastia - 1b, juvenile uterine bleeding - 1b 7. mature (first period) - from 18 to 30-35 years: from 14 to 3b points visceral syndrome - 2b, hypermobility of joints - 3b, vascular syndrome - 2b, valve syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome -2b, pathology of the organs of vision - 2b, cosmetic syndrome - 2b, bronchopulmonary syndrome - 2b, vertebrogenic syndrome - 2b , foot pathology syndrome - 2b, arrhythmic syndrome - 2b, mental disorders - 2b in women: uterine hypoplasia - 1b, ovarian hypoplasia - 3b, primary infertility - 1b, spontaneous abortion - 1b, miscarriage - 1b, bleeding in childbirth - 1b; in men: testicular hypoplasia - 3b, hypogonadism - 1b, microgenosomy - 1b, erectile dysfunction -2b 8. mature (second
period) from 35 to 55 years for women and from 35 to 60 years for men:
from 14 to 30 points visceral syndrome - 2b, vascular syndrome - 2b, valve syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome -2b, pathology of the organs of vision - 2b, cosmetic syndrome - 2b, bronchopulmonary syndrome - 2b, vertebrogenic syndrome - 2b, foot pathology syndrome - 2b, mental disorders - 2b,
arrhythmic syndrome - 2b, hernias of the anterior abdominal wall -2b in women: prolapse of the walls of the vagina - 1b, prolapse of the uterus 1-3 tbsp. in men: benign prostatic hyperplasia -1b,
-2b erectile dysfunction 9. advanced age - from 55-60 to 75 years for women and men: from 10 to 24 points visceral syndrome - 2b, vascular syndrome - 2b, valve syndrome - 3b, hernias of the anterior abdominal wall - 2b, arrhythmic syndrome - 2b, pathology of the organs of vision - 2b, bronchopulmonary syndrome - 2b, vertebrogenic syndrome - 2b, mental disorders - 2b in women: prolapse of the walls of the vagina - 1b, prolapse of the uterus - 1b, sclerosis of the gonads - 3b; in men: benign prostatic hyperplasia - 1b, erectile dysfunction -2b 10. senile - from 75 years and older: from 10 to 23 points visceral syndrome - 2b, vascular syndrome - 2b, valve syndrome - 3b, hernias of the anterior abdominal wall -2b, arrhythmic syndrome - 2b, bronchopulmonary syndrome - 2b, pathology of the organs of vision - 2b, vertebrogenic syndrome - 2b, mental disorders - 2b in women: genital prolapse - 1b, genital sclerosis - 3b;
in men: benign prostatic hyperplasia - 1b, erectile dysfunction - 2b Note: Manifestations of connective tissue dysplasia in childhood are characterized by symptoms, and in adulthood are summarized in syndromes.

With age, the number of symptoms in the syndrome increases. Symptoms detected in primary school age become constant in subsequent age periods. For example, with vascular syndrome, inconsistent symptoms are changes in blood vessels, accompanied by an increase in tone in the system of large, small arteries and arterioles, with a decrease in the volume and speed of filling of the arterial bed, with a decrease in venous tone and excessive deposition of blood in the peripheral veins, manifest with age of telangiectasias, endothelial dysfunctions, damage to the arteries of muscle and mixed types (bifurcation-hemodynamic aneurysms). In the future, with vascular syndrome, persistent symptoms such as heart attacks and strokes appear. Vascular syndrome manifests in older school age and adulthood (in the first period), progressing with increasing age of patients. With a syndrome of pathology of the organ of vision, a constant symptom of myopia joins with such an unstable symptom as astigmatism.

The list of syndromes included in connective tissue dysplasia must necessarily include an assessment of sexual development, since DST syndrome is endocrinopathy associated with insufficient intrauterine sexual differentiation, and is always accompanied by signs of sexual insufficiency, fully consistent with patients with delayed sexual development, which was identified by the results of this research.

Table 2 presents the main and control groups consisting of boys and girls aged 14 to 17 years. In the main group - those studied with clinical manifestations of connective tissue dysplasia, confirmed by the results of the CPC test (10% cetylpyridinium chloride), which determines the content of total glycosaminoglycans in the urine. In the control group, the subjects had no clinical manifestations of connective tissue dysplasia. CPC analyzes of urine in this group are low. The total volume of testicles and ovaries of boys and girls from the main group significantly exceeds the total volume of testes and ovaries of boys and girls from the control group, which is confirmed by the Fisher statistical criterion used to determine significant differences between the mean values, p <0.05.

table 2 The size of the testicles and ovaries of children and adolescents with connective tissue dysplasia No. Indicators Boys 14-17 years old Girls 14-17 years old main group (n = 10). control group (n = 10) main group (n = 10) control group (n = 10) one age M ± m 15.78 ± 1.09 15.78 ± 1.16 15.51 ± 1.04 16.11 ± 1.16 2 total volume of testes and ovaries cm ³ M ± m 15.09 ± 5.16 N = 16.47 to 39.85 cm ³ 18.96 ± 3.22 12.77 ± 1.04 N = 13.8 ± 0.6 to 17.6 ± 0.8 cm ³ 14.96 ± 1.88

Where N - normal indicators of the total volume of testicles and ovaries (Mitkov V.V., Zubareva E.A. et al. Practical Guide to Ultrasound Diagnostics, M .: Medicine, 2002, p. 88; Pediatric Ultrasound Diagnostics: Guide for Doctors / Under the editorship of Pykov M.I., Vatolina K.V. M .: Vidar, 2001), n - number of patients. M ± m average value and deviation. In previously published studies on connective tissue dysplasia, hypoplasia of the testes and ovaries was not observed among the phenotypic signs of DST. In andrology, gonadal hypoplasia was seen as a sign of a weak sexual constitution, but was not associated with DST. When examining children and adolescents with syndromic disorders, which are constant signs of DST, the present invention revealed a decrease in the total testicular volume in boys and ovaries in girls.

A comparative analysis of the proposed method with the prototype shows that the claimed method for the diagnosis of DST differs in the introduction of new age and gender criteria associated with a delay in the functioning of the sex glands, which are determined visually in boys by a decrease in testicular volume, and in girls of the ovaries, as well as a delay in the development of secondary sexual characteristics, with confirmation ultrasound results in the study, as can be seen from the results presented in table 2. In the future, gender and age changes in patients DST persist throughout life. In previous studies related to the diagnosis of DST, among the phenotypic signs of DST, a decrease in the total volume of the testes and ovaries was not indicated, and in the inventive method, based on the study, the delay in the development of the gonads is constant. While the diagnosis of the prototype is highly specific: you need to know the changes in the palpebral fissures, eyelids, sclera, iris, lens, retinal vessels, visual impairment, combined with skeletal and cardiological changes, hypermobility of joints, stigmas of dysembryogenesis.

Clinical examples of the method.

Example 1. Patient O., age 3 weeks. Diagnosis: hip dysplasia. Funnel chest. Installation torticollis. Hypospadias. Micropenis From the genealogical history it is known: grandmother and grandfather on the part of the mother were diagnosed with vascular disease, grandfather on the part of the father had heart disease, and the grandmother had a spinal disease. The boy’s father has a pathology of vision. In the mother of the child, mitral valve prolapse. From the anamnesis of life: a boy from the first pregnancy, proceeding against the background of a burdened obstetric history, cytomegalovirus infection detected in the second half of pregnancy, medical treatment, outpatient. The child is the second of twins, the first girl died on the second day after birth from a congenital heart disease. Delivery premature, at 32 weeks, by cesarean section. A neonatologist exposed a funnel chest in a maternity hospital. At the age of 2 weeks, dysplasia of the hip joints was revealed. The child was consulted by a urologist, diagnosed with hypospadias, capitate. Micropenis Thus, the age-related clinical manifestations of connective tissue dysplasia in this example are manifested according to 3 symptoms out of 9 possible at the neonatal age (from 0 to 3-4 weeks): hip dysplasia - 1b, installation torticollis - 1b, funnel-shaped chest - 1b. Symptoms of the reproductive system amounted to 2 points. The sum is 5 points, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 2. Patient K., infancy. Diagnosis: hemangioma of the scalp, fast-growing. Umbilical hernia. Synechia of the labia. From the genealogical history it is known: my mother’s grandmother had a heart disease and duodenal ulcer, my mother’s grandfather died after spinal surgery. Grandfather on the part of his father is depressed, with complete suicide, grandmother has joint disease. The girl’s father has a congenital heart disease. Mom has an extra chord. From the anamnesis of life: a child from a second pregnancy proceeding against the background of a burdened obstetric history, the first pregnancy froze at a period of 12 weeks. Real pregnancy proceeded against the background of chronic nicotine intoxication. Delivery premature, at 36 weeks, by cesarean section. In the maternity hospital, a neonatologist exposed an installation torticollis, a funnel-shaped chest, a hemangioma of the scalp. At the age of one month, a pediatrician was diagnosed with umbilical hernia, synechia of the labia minora. After discharge from the maternity hospital, the girl was disturbed by periodic vomiting and frequent spitting up. Thus, the age-related clinical manifestations of connective tissue dysplasia in this example are manifested in 6 out of 13 possible symptoms in infancy (from 3-4 weeks to 12 months): hip dysplasia - 1b, installation torticollis - 1b, funnel chest cell - 1b, hemangioma - 1b, umbilical hernia - 1b, regurgitation and vomiting syndrome - 1b. Symptoms of the reproductive system amounted to 1 point. The total amount is 7 points, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 3. Patient S., 2 g. 6 m., Preschool age. Diagnosis: inguinal hernia and lipoma of the white line of the abdomen. Funnel chest. Hypospadias, capitate form. Micropenis From the genealogical history it is known: my mother’s grandfather had periodic operations for recurrent hernias of the anterior abdominal wall of the abdomen, and mother’s grandmother was treated for gynecological diseases. At the grandfather's side, her father operated on a hernia of the spine, and her grandmother underwent surgery in connection with stenting of the coronary vessels. The boy’s father was operated on for varicocele. The mother of the child was treated for varicose veins of the lower extremities. From the anamnesis it is known: a child from a third pregnancy proceeding against the background of a burdened obstetric history: the first pregnancy ended in a medical abortion. The second pregnancy ended in the birth of a healthy, full-term girl. But at the age of one year, she died of laryngotracheitis, laryngeal stenosis. Real pregnancy proceeded against the background of moderate gestosis in the second half of pregnancy, inpatient treatment. In the maternity hospital, a neonatologist exposed a funnel chest (1b), hemangioma in the back (1b), and installation torticollis (1b). At the age of five months, hemangioma independently regressed. Until the age of three months, the boy was disturbed by periodic regurgitation (1b). The boy was consulted by a urologist at the age of 1 year, the diagnosis was made: hypospadias, capitate (1b) and micropenis (1b). Operated at the age of 1.5 years for hypospadias. At the age of 2, she was consulted by a surgeon regarding complaints of chronic constipation (1b). At the age of 2.5 years, he was operated on for inguinal hernia (1b) and lipoma of the white line of the abdomen. Thus, the clinical manifestations of connective tissue dysplasia, presented in this example, are manifested by 2 symptoms out of 13 possible in this pre-school age (from 1 year to 3 years): chronic constipation - 1b, funnel-shaped chest - 1b. Symptoms of dysplasia from the neonatal period to the present age period were 6 points. Changes in the reproductive system 2 points. The total amount is 10 points, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 4. Patient K., preschool age, 5 l. Diagnosis: chronic constipation. Violation of posture. Flat valgus feet. Mitral valve prolapse with 1st degree regurgitation. Phimosis. Testicular hypermobility. Enuresis. From the genealogical history it is known: my mother’s grandmother had a spinal disease, my mother’s grandfather was operated on for a hernia of the spine. Grandfather on the part of his father has a heart condition. The boy’s father has a pathology of vision. The mother of the child was operated on for cholelithiasis, the postoperative period is complicated by a postoperative hernia. From the anamnesis of life: a child from the first pregnancy proceeding against the background of a burdened obstetric history: moderate toxicosis of the first half of pregnancy, moderate gestosis in the second half of pregnancy, inpatient treatment in both cases. Delivery is urgent, at 39 weeks. In the maternity hospital, a neonatologist was diagnosed with an installation torticollis (1b). Until 3 months of age, torticollis regressed. Up to a year, the boy was disturbed by periodic regurgitation (1b). Up to a year, he was observed by an orthopedist about hip dysplasia on the right (1b). The child received treatment from a pediatrician from the age of one for chronic constipation and nocturnal enuresis. Consulted by an orthopedist at 4 years of age, revealed a violation of posture, flat-valgus feet. At the age of 4.5 years, he was consulted by a cardiologist, mitral valve prolapse with regurgitation of 1 degree was determined on an ultrasound of the heart. Consulted by a urologist at the age of 4.5 years, diagnosed with phimosis, testicular hypermobility. Thus, the clinical manifestations of connective tissue dysplasia presented in this example are manifested in 5 out of 14 possible symptoms in this preschool age (from 3 to 6 years): chronic constipation - 1b, nocturnal enuresis - 1b, flat valgus feet - 1b, violation of posture - 1b, mitral valve prolapse - 3b. Dysplastic symptoms from the neonatal period to the present age period amounted to 3 points. Changes in the reproductive system 2 points. The total amount is 12 points, out of 14 possible, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 5. Patient T., 10 years old, primary school age. Diagnosis: congenital S-shaped scoliosis of the thoracic region. Hypermobility of the joints. Flat valgus feet. X-shaped deformation of limbs. Extrasystole, paroxysmal tachyarrhythmia. Duodeno-gastric reflux. Astigmatism. From the genealogical history it is known: my grandfather had a stomach disease on his mother’s side, and his mother’s grandmother operated on for a hernia of the spine. Grandmother on the father’s side has varicose veins of the lower extremities, grandfather has arterial hypertension. From the anamnesis of life: a child from a second pregnancy proceeding against the background of a burdened obstetric anamnesis: the first pregnancy is an ectopic pregnancy, left tubectomy, mild toxicosis of the first half of a real pregnancy, in the second half of pregnancy there is a threat of termination, inpatient treatment. Delivery is urgent, at 38 weeks. In the maternity hospital, a neonatologist was diagnosed with a funnel chest, hemangioma of the superciliary region on the left (1b). It was observed by an orthopedist up to 1.5 years of age due to dysplasia of the hip joints (1b), a funnel-shaped chest. At 8 months of age, sclerosis was performed for hemangiomas of the superciliary region on the left. On FGDS at 7 years old revealed duodeno-gastric reflux. Consulted by an orthopedist at 7 years old, impaired posture, flat-valgus feet, hypermobility of joints. At the age of 7 years on the ECG revealed extrasystole and paraxismal tachycardia. An ultrasound of the heart revealed an additional chord. At 7 years old, an optometrist diagnosed astigmatism. Ultrasound of the ovaries at 10 years of age described hypoplasia of both ovaries. The total volume of the ovaries is 6.6 cm ³ . At 10 years old, the orthopedist was diagnosed with S-shaped scoliosis of the thoracic region, X-shaped deformation of the limbs. Consulted by a psychiatrist at the age of 10 years, asthenic syndrome was identified. Thus, the clinical manifestations of connective tissue dysplasia presented in this example are manifested in 10 syndromes out of 10 possible primary school age (from 7 to 11 years): visceral syndrome - 2b, joint hypermobility - 3b, valve syndrome - 3b asthenic syndrome - 2b, thoracodiaphragmatic syndrome - 2b, pathology of the organs of vision - 2b, cosmetic syndrome - 2b, bronchopulmonary syndrome - 2b, arrhythmic syndrome - 2b, foot pathology syndrome - 2b. Dysplastic symptoms from the neonatal period to the present age period amounted to 2 points. Changes in the reproductive system 3 points. The total amount is 25 points out of 26 possible, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 6. Patient P., 15 years old. Senior school age. Diagnosis: Marfan syndrome. Aneurysm of the ascending aorta. Mitral valve prolapse, grade 2. Mitral regurgitation 2 tbsp. Aortic valve insufficiency 1 tbsp. Circulatory disturbance of 1 degree. Vegetative-vascular dysfunction. Subluxation of the lens of both eyes. Amblyopia of a high degree of both eyes. Scoliosis of the thoracic spine 3 tbsp. Bronchial asthma. Flat valgus feet. Spasm of accommodation. Asthenic syndrome. From the genealogical history it is known: grandfather and grandmother have a heart disease on the father’s side, and mother’s spinal disease on the grandfather’s side. The boy’s father has a stomach disease, pathology of vision. The mother of the child has an extra chord in her heart. From the anamnesis of life: a child from the first pregnancy, proceeding against the background of a burdened obstetric history, chronic fetal hypoxia, with the threat of interruption for periods of 14 and 28 weeks against the background of inpatient treatment. In the neonatal period, installation torticollis (1b), heart murmur, micropenis (1b), cryptorchidism on the right (1b) were revealed. At the age of one year, he received gymnastics about an installation torticollis and chest massage. It was observed up to a year by a pediatrician with complaints of systematic regurgitation and periodic vomiting (1b). The surgeon diagnosed hemangioma in the upper eyelid (1b), which appeared at 3 months and regressed to 2 years of age. Up to 3 years of age, the child had frequent colds, complicated by bronchial obstructive syndrome. At preschool age, complaints of chronic constipation (1b) and nocturnal enuresis (1b) were noted. At the age of 5 years, the boy was examined at the place of residence by an orthopedic surgeon for violation of posture and flat valgus feet. At the age of 7, when examined by a urologist, phimosis (1b) and testicular hypermobility (1b) were revealed in front of the school. An examination by a cardiologist on ultrasound revealed mitral valve prolapse with 1st degree regurgitation. Optometrist exposed spasm of accommodation. An allergist-immunologist was diagnosed with bronchial asthma, atopic, mild. From the age of 8, an orthopedist exhibited scoliosis of the thoracic spine of the 1st degree, joint hypermobility syndrome, according to Beighton 12 points. The expressed manifestations of the cosmetic syndrome were diagnosed: dysplastic-dependent dysmorphies of the maxillofacial region (malocclusion, Gothic palate, severe facial asymmetries); X-shaped deformation of limbs; changes in the skin (thin, translucent and easily injured skin, and its increased extensibility). On FGDS revealed duodeno-gastric reflux. At the age of 14 years, an ultrasound of the prostate revealed hypoplasia, an ultrasound of the testicles revealed testicular hypoplasia. The size of the testicles corresponds to 9 years. At the consultation of the andrologist, cryptorchidism, inguinal ectopy of the right testicle were revealed. Hydatide of the right testicle. Delayed sexual development (2b). The formula for sexual development is G3; A2; P3. Thus, the clinical manifestations of connective tissue dysplasia presented in this example are manifested in 12 syndromes out of 12 possible in this senior school age (from 12 to 17-18 years): visceral syndrome - 2b, joint hypermobility - 3b, vascular syndrome - 2b, valvular syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome - 2b, pathology of the organs of vision - 2b, cosmetic syndrome - 2b, bronchopulmonary syndrome - 2b, arrhythmic syndrome - 2b, foot pathology syndrome - 2b. Dysplastic symptoms from the neonatal period to the present age period amounted to 9 points. Changes in the reproductive system are 5 points. The total amount is 38 points out of 33 possible, i.e. the total score corresponds to differentiated connective tissue dysplasia, Marfan syndrome.

Example 7. Patient A., 17 l. Senior school age. Diagnosis: scoliosis 2 tbsp., On the right, progressive form. Left atrial focal tachycardia. Heart rhythm disturbance: atrial rhythm migration. Prolapse of the mitral, tricuspid valves with mitral regurgitation 1 tbsp. Circulatory disorders 1 tbsp. The syndrome of autonomic dysfunction. Mastocytosis, systemic form, remission. Longitudinal flatfoot. Asthenic syndrome. Astigmatism. Family history: grandfather on the father's side has a spinal disease. Maternal grandfather suffers from bronchial asthma. My mother’s grandmother has a heart condition. Dad has a decrease in vision. Mom has arterial hypertension. From the anamnesis of life: in the neonatal period, dysplasia of the hip joints was exposed (1b), a heart murmur was heard. At the age of 5 months, periodic regurgitation and vomiting were noted (1b). At the age of 3, an umbilical hernia was diagnosed (1b). In preschool age, frequent colds were noted. When applying to the school, the orthopedist exposed a violation of posture, flat feet. A cardiologist diagnosed cardiac arrhythmias and mitral valve prolapse with mitral regurgitation 1 tbsp. From the age of 7, the girl is observed by a pediatrician about biliary dyskinesia of the hypomotor type. At the age of 13, the orthopedist was diagnosed with scoliosis of 2 tbsp., On the right, a progressive form, hypermobility of joints, according to Beight 10 points. Menzis from 15.5 years old, irregular, once received inpatient treatment for juvenile uterine bleeding. The total volume of the ovaries is 10.6 cm, the sexual development of Ma2P2Ax2Me +, on ultrasound of the pelvic organs, hypoplasia of the ovaries and uterus. Diagnosed with delayed sexual development. Thus, the clinical manifestations of connective tissue dysplasia presented in this example can be traced in 9 syndromes out of 12 possible in this senior school age from 12 to 17-18 years old): visceral syndrome - 2b, joint hypermobility - 3b, vascular syndrome - 2b, valvular syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome - 2b, pathology of the organs of vision - 2b, cosmetic syndrome - 2b, arrhythmic syndrome - 2b, foot pathology syndrome - 2b. Dysplastic symptoms from the neonatal period to the present age period amounted to 3 points. Changes in the reproductive system 7 points. The total amount is 32 points out of 33 possible, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 8. Patient K., 28 l. Mature age (first period). Diagnosis: S-shaped scoliosis 3 tbsp. left, operated. Heart rhythm disturbance: isolated extrasystoles. Chronic gastroduodenitis without exacerbation. Mitral valve prolapse with regurgitation 1 tbsp. Longitudinal flatfoot. Asthenic syndrome. Myopia of a high degree. Family history: grandfather and grandmother on the father's side died of a heart attack. Maternal grandfather died after spinal surgery. My mother’s grandmother has heart disease, myopia, gynecological diseases. The young man’s father has myopia, joint disease, prostate disease. The mother has hypertension. From the anamnesis of life: in the newborn period, a heart murmur was heard. Under the age of one year, periodic regurgitation and vomiting were noted (1b). At the age of 2, the patient was operated on for an inguinal-scrotal hernia (1b). At the age of 7, an orthopedist was diagnosed with S-shaped scoliosis of the 2nd degree on the left, flat feet. A cardiologist revealed a violation of the heart rhythm and prolapse of the mitral valve with regurgitation of 1 tbsp. From the age of 10, the young man was observed by a pediatrician about chronic gastroduodenitis. At age 14, an orthopedist was diagnosed with S-shaped scoliosis of 3 tbsp. left, progressive form. Hypermobility of joints, according to Beighton 12 points. At 16, he was operated on for varicocele (1b). Consulted by andrologist, development formula: G3; A2; P3. The total testicular volume is 11.08 cm ³ , testicular hypoplasia, delayed sexual development (2b). An andrologist is currently observing erectile dysfunction. Thus, the clinical manifestations of connective tissue dysplasia presented in this example are manifested in 7 syndromes out of 14 possible in this mature (first period) age (18 to 30 - 35 years old): visceral syndrome - 2b, joint hypermobility - 3b, valve syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome - 2b, pathology of the organs of vision - 2b, foot pathology syndrome - 2b, arrhythmic syndrome - 2b. Symptoms from the neonatal period to the present age period were 5 points. Symptoms of the reproductive system amounted to 5 points. The total amount is 28 points, out of 34 possible, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 9. Patient O., 34 g. Mature age (first period). Diagnosis: S-shaped lumbar kyphoscoliosis 2 tbsp. Hypertension of the 1st degree. Left atrial focal tachycardia. Heart rhythm disturbance. Mitral valve prolapse with regurgitation 1 tbsp. Nephroptosis Chronic pyelonephritis without exacerbation. Urolithiasis disease. Asthenic syndrome, moderate. Mild myopia. Primary infertility. Family history: grandfather and grandmother on the father's side died of a heart attack. Maternal grandfather died of prostate cancer. My mother’s grandmother completed suicide. The father has hypertension, prolapse of the kidney, chronic pyelonephritis, urolithiasis. The mother has hypertension, high myopia, gynecological diseases. From the anamnesis of life: at the age of up to a year, several months were treated for hip dysplasia (1b). From the age of one year, the girl was observed by a pediatrician about heart murmur. From 2 years old, ultrasound revealed kidney prolapse, chronic pyelonephritis. At the age of 3, she was operated on for an umbilical hernia (1b). From the age of 7, an orthopedist exposed postural disturbance, flat feet. A cardiologist diagnosed cardiac arrhythmias and mitral valve prolapse with regurgitation of 1 tbsp. From the age of 7, a pediatrician observes chronic gastroduodenitis. At the age of 14, an orthopedist was diagnosed with S-shaped lumbar scoliosis of 1 tbsp. Hypermobility of the joints. Beiton score 10 points. Increased vulnerability, hyper-stretch of the skin. Menzis from the age of 16, irregular, has repeatedly received inpatient treatment for juvenile uterine bleeding (1b). The total volume of the ovaries is 10.7 cm ³ , ultrasound revealed hypoplasia of the uterus and ovaries. Primary infertility exhibited at 30 years. A cardiologist diagnosed hypertension of 1 degree in 32 years. Thus, the clinical manifestations of connective tissue dysplasia presented in this example are manifested in 9 syndromes out of 13 possible in this mature (first period) age (from 30 - 35 years to 55 years): visceral syndrome - 2b, joint hypermobility - 3b, valve syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome - 2b, visual pathology - 2b, cosmetic syndrome - 2b, foot pathology syndrome - 2b, arrhythmic syndrome - 2b. Intermittent symptoms were 3b. Symptoms of the reproductive system amounted to 5 points. The total amount is 28 points, out of 34 possible, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 10. Patient P., 44 g. Mature age (second period). Diagnosis: coronary heart disease, unstable angina pectoris 2 functional class. Postinfarction cardiosclerosis (heart attack in 2012). Hypertension of the 3rd degree. Risk 3. Chronic heart failure 2A std. S-shaped thoracic scoliosis 3 tbsp., Right. Heart rhythm disturbance. Chronic esophagitis without exacerbation. Asthenic syndrome, moderate. Mild myopia. Benign prostatic hyperplasia. Family history: grandfather and grandmother on the father's side died of heart disease. Maternal grandfather died of prostate cancer. My mother’s grandmother died of a stroke. His father has a pathology of vision, a disease of the kidneys and prostate gland. The mother has hypertension and gynecological diseases. From the anamnesis of life: in preschool age, the patient was operated on for phimosis (1b) and inguinal hernia (1b). At primary school age, an orthopedist exposed to a violation of posture, flat feet. From the age of 10, he was observed by a pediatrician about chronic esophagitis. At the age of 14, the orthopedist was diagnosed with S-shaped chest scoliosis of the 2nd degree on the right. At the age of 15, a cardiologist diagnosed juvenile arterial hypertension 1 tbsp. An ultrasound of the heart was diagnosed with an additional chord. On an ECG, sinus arrhythmia. At the age of 16, an endocrinologist exposed obesity of 1 st, acne, and increased skin extensibility (2b). At the age of 1b he was operated on for varicocele on the left (1b), at 35 he turned to an andrologist for erectile dysfunction (2b) and benign prostatic hyperplasia. At 42, he suffered a myocardial infarction. Thus, the age-related clinical manifestations of connective tissue dysplasia presented in this example are manifested in 8 syndromes out of 14 possible in this mature (second period) age (30-35 to 60 years): visceral syndrome - 2b, vascular syndrome - 2b, valve syndrome - 3b, asthenic syndrome - 2b, thoracodiaphragmatic syndrome -2b, pathology of the organs of vision - 2b, foot pathology syndrome - 2b, arrhythmic syndrome -2b. Symptoms of DST from childhood to the present age period were 7b. Symptoms of the reproductive system amounted to 1 point. The total amount is 25 points, out of 30 possible, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 11. Patient M., 63 years old. Elderly age. Diagnosis: coronary heart disease, stable angina pectoris 3 functional class. Postinfarction cardiosclerosis (myocardial infarction in 2002 and 2009). Chronic aortic aneurysm. Hypertension of the 3rd degree. Risk 4. Chronic heart failure stage 2A. Type 2 diabetes mellitus, mild subcompensation, S-shaped thoracolumbar kyphoscoliosis 3 tbsp. From the family history it is known that both grandmothers died at the age of 60 from heart disease. The patient’s mother had a disease of the spine, in her youth she worked in the circus as a circus gymnast, at an older age she suffered from bronchial asthma. My father noted frequent fractures of the limbs, heart and joint disease. From the history of life, it is known that at the age of 2 years the patient was operated on for an umbilical hernia (1b). In elementary school, she was involved in athletics, but after a knee injury, she had to stop playing sports. It grew tall, thin, and up to adulthood increased joint flexibility was noted (3b). She suffered from acne, and there are currently scars on the skin in the cheek area, especially in the chin area (2b). In high school, weak myopia was detected, which progressed over time. There were periodic abdominal pain associated with food, headaches worried. Menzis from 16 years old, with bleeding (1b), symptomatic treatment. The first pregnancy at the age of 27 years ended in an early miscarriage (1b). The second pregnancy at 34 years ended in premature birth, the child died in infancy. Progressive osteochondrosis of the lumbar spine exposed at 35 years old, from the age of 37 receives treatment for type 2 diabetes. Hypertension since 39 years. Coronary heart disease since 45 years. He has been receiving treatment for angina pectoris since 52 years old. Observed by a neurologist about asthenoneurotic syndrome since 50 years. From the age of 50, she has been observed by a gynecologist about uterine prolapse. Ultrasound of the abdominal organs revealed nephroptosis 2 tbsp. Postinfarction cardiosclerosis at 53 years. Ultrasound of the pelvic organs in 60 years of ovaries was not determined. Thus, the clinical manifestations of connective tissue dysplasia, presented in Table 1 in this example, are manifested by 5 syndromes out of 10 possible in this elderly age (from 55-60 years to 75 years): visceral syndrome - 2b, vascular syndrome - 2b, pathology of the organs of vision - 2b, vertebrogenic syndrome - 2b, mental disorders - 2b. Symptoms from childhood to the present age period were 8b. The total amount is 18 points, out of 23 possible, i.e. the total score corresponds to undifferentiated dysplasia of the connective tissue.

Example 12. Patient S., 77 years old. Senile age. Diagnosis: coronary heart disease. Unstable angina pectoris. Postinfarction cardiosclerosis. Myocardial infarction in 2010. Stenosing atherosclerosis of the coronary arteries. Hypertension 3 tbsp., Risk 4. Chronic heart failure 2A tbsp., 3 functional class. Type 1 diabetes mellitus, mild course. S-shaped scoliosis of 4 degrees. Osteochondrosis of the lumbar spine. Herniated disc L5 S1. Condition after removal of a herniated disc. Nephroptosis Coronary kidney disease. Stenosing atherosclerosis of the renal arteries: occlusion of the left, stenosis of 90% of the right renal artery. Urolithiasis disease. Stones of the right kidney. Myopia is moderate. Alimentary-constitutional obesity 1 tbsp. Astheno-depressive syndrome. From the genealogical history it is known that the patient’s mother had joint disease, decreased vision, hypertension in retirement age and heart disease. Father suffered from gastric ulcer, died of prostate cancer. From the history of life it is known that from childhood the patient had phimosis (1b) and enuresis (1b) before starting school. At preschool age, he was operated on for an inguinal-scrotal hernia (1b). In adolescence, he was successfully involved in athletics, due to increased flexibility in the joints (3b), but after graduation, patient C. no longer did sports. He was commissioned from the army about urolithiasis. Since 30 years, suffers from erectile dysfunction (2b). From the age of 40, he has been worried about progressive S-shaped scoliosis, osteochondrosis of the lumbar region (2b). At 50, she was operated on for a herniated disc L5 S1. He has been receiving treatment by a neurologist for astheno-depressive syndrome since he was 50 years old. From the age of 55 he suffers from ischemic kidney disease, hypertension. From the age of 60, he has been observed by a cardiologist about stenotic atherosclerosis of the coronary arteries, and an endocrinologist about type 1 diabetes. At age 64, he was diagnosed with unstable angina, post-infarction cardiosclerosis at age 20, and grade 2 knee arthrosis. At the age of 65, the andrologist exposed benign prostatic hyperplasia. Thus, the clinical manifestations of connective tissue dysplasia presented in this example are manifested by 5 syndromes out of 10 possible in this senile age (from 75 years): visceral syndrome -2b, vascular syndrome - 2b, pathology of the organs of vision - 2b, vertebrogenic syndrome -2b, mental disorders - 2b. Symptoms from childhood to the present age period were 10b. Symptoms of the reproductive system amounted to 1 point. The total amount corresponds to 21 points, out of 23 possible, i.e. undifferentiated connective tissue dysplasia.

Thus, the proposed new criteria and the scoring system for age groups allow for more objective diagnosis of such differentiated forms of connective tissue dysplasia as Ehlers-Danlo syndrome, Marfan syndrome and others, as well as undifferentiated forms in which the set of clinical signs does not fit into any from hereditary monogenic diseases.

Claims (1)

A method for the age-related diagnosis of connective tissue dysplasia syndrome (DST), including identifying and scoring the manifestations of DST and additionally the manifestations of DST in the reproductive system, as shown in table 1, the subsequent summation of the scores and the establishment of DST in each case with the following points: (from 0 to 3-4 weeks) from 4 to 9 points; for infancy (from 3-4 weeks to 12 months) from 7 to 11 points; for the pre-school period (from 1 year to 3 years) from 8 to 13 points; for the preschool period (from 4 to 6 years) from 9 to 14 points; for primary school age (from 7 to 11 years) from 11 to 26 points; for high school students (from 12 to 17-18 years old) from 12 to 33 points; for adulthood (first period from 18 to 30-35 years) from 14 to 36 points; for adulthood (the second period from 35 to 55 years for women and from 35 to 60 years for men) from 14 to 30 points; for the elderly (from 55-60 to 75 years for women and men) from 10 to 24 points; for senile age (from 75 and older) from 10 to 23 points; in this case, if the obtained total score exceeds the lower limit, then establish the syndrome of undifferentiated DST, and if the obtained total score exceeds the upper limit, then set the syndrome of differentiated DST.